Gene Therapy Approaches for Lysosomal Storage Disease: Next-Generation Treatment

Byrne, Barry J.; Falk, Darin J.; Clément, Nathalie; Mah, Cathryn

doi:10.1089/hum.2012.140

Cited by 45 publications

(36 citation statements)

References 74 publications

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“…Numerous virus-mediated gene therapy studies, mostly designed to restore the missing enzyme activity, have shown varying degrees of correction of lysosomal storage in vitro and in vivo in LSD animal models, using various viral vectors. 27 Recombinant adeno-associated virus (rAAV) has been a favored vector for gene delivery because it is non-pathogenic, with demonstrated long-term expression in the CNS and periphery. 27,28 The recent finding of trans-BBB neurotropism of AAV9 offers an effective solution for CNS gene therapy, showing great potential for the treatment of LSDs and other neurological diseases.…”

Section: Mucopolysaccharidosis (Mps) Iiib (Online Mendelian Inheritanmentioning

confidence: 99%

“…27 Recombinant adeno-associated virus (rAAV) has been a favored vector for gene delivery because it is non-pathogenic, with demonstrated long-term expression in the CNS and periphery. 27,28 The recent finding of trans-BBB neurotropism of AAV9 offers an effective solution for CNS gene therapy, showing great potential for the treatment of LSDs and other neurological diseases. [29][30][31][32][33] A single systemic delivery of rAAV9 vectors can lead to global CNS and widespread somatic restoration of enzyme activity, correction of lysosomal storage pathology, and functional neurological benefits in mice with MPS IIIB or IIIA.…”

Section: Mucopolysaccharidosis (Mps) Iiib (Online Mendelian Inheritanmentioning

confidence: 99%

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Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery

Meadows

Ware

et al. 2017

Molecular Therapy

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Mucopolysaccharidosis (MPS) IIIB is a lysosomal storage disease with complex CNS and somatic pathology due to a deficiency in a-N-acetylglucosaminidase (NAGLU). Using global metabolic profiling by mass spectrometry targeting 361 metabolites, this study detected significant decreases in 225 and increases in six metabolites in serum samples from 7-monthold MPS IIIB mice, compared to wild-type (WT) mice. The metabolic disturbances involve virtually all major pathways of amino acid, peptide (58/102), carbohydrate (18/28), lipid (111/139), nucleotide (12/24), energy (2/9), vitamin and cofactor (11/16), and xenobiotic (11/28) metabolism. Notably, the reduced metabolites included eight essential amino acids, vitamins (C, E, B2, and B6), and neurotransmitters (serotonin, glutamate, aspartate, tryptophan, and N-acetyltyrosine). The metabolic impairments appear to emerge early during disease progression before the age of 2 months. Importantly, the restoration of NAGLU activity with an intravenous (i.v.) injection of rAAV9-hNAGLU vector led to near-complete correction of all serum metabolite abnormalities, with 201 (87%) metabolites normalized and 30 (13%) over-corrected. While the mechanisms are unclear, our data demonstrate that the lack of NAGLU activity triggers profound functional metabolic disturbances in MPS IIIB. These metabolic impairments respond well to a systemic rAAV9-hNAGLU gene delivery, supporting the surrogate biomarker potential of serum metabolomic profiles for MPS IIIB therapies.

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Section: Mucopolysaccharidosis (Mps) Iiib (Online Mendelian Inheritanmentioning

confidence: 99%

Section: Mucopolysaccharidosis (Mps) Iiib (Online Mendelian Inheritanmentioning

confidence: 99%

Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery

Meadows

Ware

et al. 2017

Molecular Therapy

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“…ERT requires a large dose of enzyme (20-40 mg/kg) once every 1-2 weeks to have therapeutic benefit. [4][5][6][7] material (CRIM)-negative. 12,13 CRIM status is indicative of the amount of protein expressed because of the patient's GAA mutation.…”

mentioning

confidence: 99%

Copackaged AAV9 Vectors Promote Simultaneous Immune Tolerance and Phenotypic Correction of Pompe Disease

et al. 2016

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“…Recombinant viral-and nonviral-based gene transfer vectors have been employed that were delivered either directly into the CNS or into the systemic circulation (43)(44)(45)(46). Transplantation of stem cells that were genetically modifi ed ex vivo has also shown promise.…”

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confidence: 99%

Gene therapy for the neurological manifestations in lysosomal storage disorders

Cheng¹

2014

Journal of Lipid Research

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precise mechanistic links between these altered biochemical and cellular states and disease pathophysiology and pathogenesis remain unclear. Typically, disease severity is correlated with the level of residual activity, with individuals harboring lower levels presenting with more aggressive and severe disease manifestations. A large percentage of individuals, particularly those with signifi cantly diminished lysosomal function, also exhibit CNS involvement, the extent of which is dependent on the nature of the specifi c storage metabolites and the differential sensitivity of the resident cell types to the accumulated substrates. Although individually each LSD may be relatively rare, as a group, these disorders have an incidence of approximately 1 per 5,000 live births ( 4, 5 ).Of the approximately 50 LSDs that have been identifi ed thus far, the majority (greater than 70%) exhibit significant CNS involvement ( 6 ). This fi nding is not surprising given that lysosomes and related organelles are ubiquitously present in most cell types and are involved not only in recycling cellular debris but also in maintaining cellular homeostasis ( 7-9 ). Irrespective of the LSD, these CNS diseases are typically characterized by generalized infl ammation and neurodegeneration in multiple brain regions. In a subset of the diseases, altered calcium homeostasis and oxidative stress may also contribute to the overall pathology ( 10 ). Moreover, each specifi c disease may initially present with a unique temporal and spatial alteration that is dictated by the nature of the storage metabolites prior to the development of a more generalized global derangement ( 11 ). In some diseases, the symptoms are evident in neonates, whereas in others, they become apparent only in early childhood. Consequently, some LSDs may require early therapeutic intervention to affect broad and potentially all regions of the CNS. The lysosomal storage disorders (LSDs) are a heterogeneous group of inherited metabolic diseases that result from a defi ciency in one or more of the 80 enzymes or transporters that normally reside within the lysosomal compartment ( 1-3 ). A reduction or loss of one or more of these activities results in the progressive and relentless accumulation of undegraded macromolecules, a consequent derangement of proper lysosomal and autophagosomal functions, and ultimately, cellular demise. However, the

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Gene Therapy Approaches for Lysosomal Storage Disease: Next-Generation Treatment

Cited by 45 publications

References 74 publications

Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery

Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery

Copackaged AAV9 Vectors Promote Simultaneous Immune Tolerance and Phenotypic Correction of Pompe Disease

Gene therapy for the neurological manifestations in lysosomal storage disorders

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